JPH04279522A - Medicine for regulating serum calcium concentration - Google Patents

Abstract

PURPOSE:To provide the title medicine easy to handle by patients themselves, effective for the prevention or therapies of hypercalcemia and hypocalcemia, in particular, for suppressing rapid rise in serum calcium level due to vitamin D administration. CONSTITUTION:The objective medicine containing either (A) vitamin A or (B) a mixture of vitamin A with vitamin D (pref. vitamin D2 and/or vitamin D3) at the weight ratio D/A=pref. (1:1.6) to (1:10000) (in the case of (B), pref. further containing calcium). For the therapy of hypercalcemia, vitamin A is only to be administered singly; thereby, serum calcium concentration can be reduced relatively easily and safely. For the therapy of hypocalcemia, vitamin A should be administered in combination with vitamin D; thereby, rapid rise in serum calcium concentration will be suppressed and side effects are prevented; therefore, vitamin D can be conveniently administered without the need for strictly controlling serum calcium level.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION This invention relates to the regulation of serum calcium concentration by administration of vitamin A. Specifically, the present invention relates to the prevention and treatment of hypercalcemia due to rapid increases in serum calcium levels due to administration of vitamin D, or other causes, by administration of vitamin A.

0002

[Prior Art] Calcium plays an important role in biological control such as hormone secretion and metabolic regulation. The serum calcium concentration in living organisms is strictly controlled, and is usually maintained at 9 mg to 10 mg per 100 ml of serum. When the serum calcium level falls below this level, this control function comes into play, and the intestinal tract actively takes in calcium from food, and the kidneys try to reabsorb calcium excreted in the urine. If it is still insufficient, calcium phosphate, which makes up the bones, is mobilized, thus restoring the serum calcium concentration to normal levels. On the other hand, even when the serum calcium level rises beyond the above range, the control function operates, suppressing calcium intake and increasing calcium excretion, thereby maintaining the serum calcium level at a normal value.

[0003] It is known that vitamin D is deeply involved in the above-mentioned process of controlling serum calcium concentration. Vitamin D is said to be necessary for absorption of calcium in the intestines and reabsorption of calcium in the kidneys, and the presence of vitamin D is essential for the above control function to function smoothly in order to restore the decreased calcium concentration to normal values. It is.

[0004] Generally, serum calcium concentration is 8 mg/1
Hypocalcemia is a condition in which the blood volume remains below 00 ml and does not recover.This condition is often seen in renal dialysis patients, kidney or liver cancer patients, etc., who are deficient in vitamin D. It often occurs due to an inability to reabsorb calcium from the urine. If this condition continues, the desorption of calcium phosphate from bone tissue progresses, leading to osteoporosis and the like. Therefore, in this case, it is effective to administer vitamin D to the patient, and such treatment is often performed. In this case, vitamin D includes naturally occurring vitamin D2 and vitamin D3, or vitamin D hormone [1α,25-(OH)2-D3], which is the active form of vitamin D that is hydroxylated in the liver or kidney. ],
or its prodrug [1α-(OH)-D3]
etc. are used.

On the other hand, serum calcium concentration is 11 mg/1
A state in which the blood volume remains above 00 ml and does not go down is called hypercalcemia. If this condition continues, a variety of nonspecific symptoms occur, including digestive system upset, excessive urination, stones, muscle weakness, confusion, and coma. Hypercalcemia is caused by various causes, one of which is vitamin A and D.
An example of this is excessive poisoning.

[0006]

[Problems to be Solved by the Invention] As mentioned above, vitamin D and its active metabolite, vitamin D hormone [1
[alpha],25-(OH)2-D3] and the like are used. It is also used as a treatment for cancer and psoriasis. However, when vitamin D is administered, the serum calcium concentration increases rapidly, which may cause various side effects in patients. In some cases, the level may temporarily rise above normal levels, in which case the side effects may be significant. In such cases, it is necessary to stop administering vitamin D and wait for the body's own actions to naturally lower the calcium level. During this time, vitamin D as a therapeutic agent cannot be administered to the patient, which is an important problem for the patient. Therefore, there is a need to quickly lower the rapidly increased serum calcium level so that the administration of therapeutic drugs can be continued. In addition, the rise in serum calcium concentration when administering vitamin D is extremely rapid, and the resulting side effects are significant. Dosage may need to be adjusted. That is, the current situation is that the treatment of hypocalcemia by administering vitamin D must be carried out under sufficient supervision, and there is a strong desire for the development of a simpler means of administration. Furthermore, as mentioned above, administration of vitamin D is effective in treating hypocalcemia, but no comparable effective means for treating hypercalcemia has yet been found. There is a strong desire to develop a simple means for treating hypercalcemia.

[0007]

[Means for Solving the Problems] The present inventor has discovered that vitamin A
It was discovered that this is involved in the control function of serum calcium concentration in living organisms, and this led to the present invention. Specifically, the present inventors have discovered that vitamin A contributes to lowering serum calcium levels through the above-mentioned control function, and have accomplished the present invention. Furthermore, the present inventors have discovered that when vitamin A is administered simultaneously with vitamin D, the rapid increase in serum calcium concentration caused by vitamin D is alleviated, and this has led to the present invention. That is, one aspect of the present invention provides a vitamin A preparation for preventing or treating hypercalcemia. Another aspect of the present invention is to provide a vitamin A preparation for preventing or treating the rapid increase in serum calcium concentration that often occurs when vitamin D preparations are administered. Yet another aspect of the invention provides a formulation comprising vitamin D and vitamin A for the treatment of hypocalcemia.

[0008]

[Function] According to the findings of the present inventors, when raising mammals, simply feeding feed that is deficient in calcium and vitamin D does not lower the serum calcium level;
Giving vitamin A also lowers serum calcium levels. Additionally, continued administration of standard doses of vitamin A to mammals with decreased serum calcium levels maintains the low calcium levels. Therefore, the serum calcium level adjusting drug containing vitamin A of the present invention is useful for lowering serum calcium levels. In addition, vitamin A along with vitamin D can be used in mammals with decreased serum calcium levels.
When administered, the serum calcium level recovers to normal value at a slow rate, so the serum calcium level adjusting drug containing vitamin D and vitamin A of the present invention does not cause a sudden increase in serum calcium level or an excessive state. It may be useful in treating hypocalcemia. Further, it becomes possible to continuously administer vitamin D as a therapeutic agent for cancer and other diseases without interruption.

The above action will be further explained based on the results of experiments shown below. [Experimental Method] Experimental Animals Three-week old Wistar white rats were used as experimental animals. These rats were fed a vitamin D-deficient diet for rats with the following composition (T. Suda, H. F. De
Luca andY. Tanaka, J. Nut
r. , 100, 1049 (1970)) to 5
Weekly feeding, vitamin A acetate 25mg%, vitamin E (tocopherol) 500mg%, vitamin K3
(Menadione) A group of D-deficient animals (1) was obtained by orally giving 2 to 3 drops of fat-soluble vitamins (A, E, K) dissolved in cottonseed oil at a rate of 60 mg% three times a week. Note that the dose of this vitamin is in excess compared to the standard dose. Composition of vitamin D-deficient feed for rats: dextrose
64.2% Casein (vitamin removed) 18.0 Cystine
0.20 Choline Chloride
0.20 cottonseed oil
10.00CaC
O3
1.09 equimolar PO4
0.9 Salts (Ca,
(does not contain P) 2.00 Vitamin mixture (does not contain A, D) 0.10ro
ughhage-celluflor
3.0 A D-deficient animal group (2) was obtained by feeding D-deficient feed under the same conditions and also feeding the above-mentioned fat-soluble vitamins with vitamin A removed. On the other hand, a normal animal group was obtained by feeding the above rats with standard rat feed manufactured by Oriental Kogyo Co., Ltd. for 5 weeks and administering cottonseed oil in the same manner as above.

Experimental Groups The experimental groups were Groups 1 to 9, and experiments were conducted for each group under the following conditions. Group 1 was a group of normal animals, which were fed a standard rat diet under the same conditions and administered only cottonseed oil every day. Group 2 used D-deficient animal group (2), and continued under the same conditions by feeding them with D-deficient feed and administering only cottonseed oil every day. Group 3 used D-deficient animals group (1) and was subsequently fed a D-deficient diet under the same conditions and administered a standard amount of 2000 IU of vitamin A dissolved in cottonseed oil every day. Group 4 uses D-deficient animal group (1) and receives 0.3 ml of cottonseed oil at the start of the test.
After administering 40 IU of vitamin D2 dissolved in water, D-deficient feed was subsequently given under the same conditions, but administration of vitamin A was discontinued and only cottonseed oil was administered every day. Group 5 uses the D-deficient animal group (1) and receives 0.3 ml of cottonseed oil at the beginning of the test.
After administering 40 IU of vitamin D2 dissolved in water, the mice were fed a D-deficient diet under the same conditions, and a standard amount of 2000 IU of vitamin A dissolved in cottonseed oil was administered every day. Group 6 uses the D-deficient animal group (1) and uses 0.0% cottonseed oil at the start of the test.
After administering 40 IU of vitamin D3 dissolved in 3 ml, D-deficient feed was subsequently given under the same conditions, but vitamin A was administered in an amount three times the standard amount (6000 IU) and 0.3 ml of cottonseed oil.
The solution was administered daily. Group 7 used D-deficient animal group (1) and was administered with vitamin D hormone [1α,25-(OH)2-D] dissolved in 0.3 ml of cottonseed oil at the start of the test.
After administering 40 IU of [3], D-deficient feed was subsequently given under the same conditions, but administration of vitamin A was discontinued, and only cottonseed oil was administered every day. Group 8 used D-deficient animal group (1) and was administered 40I of vitamin D hormone [1α,25-(OH)2-D3] dissolved in 0.3 ml of cottonseed oil at the start of the test.
After administering U, the mice were fed a D-deficient diet under the same conditions, and a standard amount of 2000 IU of vitamin A dissolved in cottonseed oil was administered every day. Group 9 uses D-deficient animal group (1), and after administering 40 IU of vitamin D2 at the start of the test, they are given D-deficient feed (however, all calcium content has been removed), but fat-soluble vitamins (A, E, K) was reared without feeding. The above vitamin A and vitamin D2 (or vitamin D3) or vitamin D hormone [1α, 25
-(OH)2-D3] was administered to one animal by dissolving the drug in 0.3 ml of cottonseed oil and orally administering the drug using a rat probe. As mentioned above, vitamin A should be administered daily, and vitamin D2 (or vitamin D
3) Or vitamin D hormone [1α,25-(OH
)2-D3] was administered in a single dose. In addition, vitamin D2 (
The medicinal efficacy of vitamin D3 (ergocalciferol) and vitamin D3 (cholecalciferol) is generally said to be the same.

Determination of calcium in serum Blood was collected from the tail vein of rats to obtain serum. After adding 0.5 ml of Stok La-TCA solution and 1.8 ml of ion exchange water to 0.2 ml of this serum and stirring, the mixture was heated at 3000 rpm.
Centrifuge for 10 minutes at m. Calcium was quantified in the supernatant using an atomic absorption spectrophotometer (Varian, Model AA-1275).

[Experimental Results] Tables 1 to 9 show the changes in calcium concentration for each of Groups 1 to 9, respectively.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

From Table 1, it can be seen that the average serum calcium concentration of the normal animal group is in the range of 8.23 to 9.35 mg/dl. By comparing Table 2 with Table 1, it can be seen that even if vitamin D-deficient feed is fed, the serum calcium concentration does not decrease when vitamin A is not fed. By comparing Table 3 with Table 2, it was found that the D-deficient animal group (2), which was fed vitamin D-deficient feed and fat-soluble vitamins (vitamins E and K) that do not contain vitamin A, had normal serum calcium levels. D containing fat-soluble vitamins (vitamins A, E, K), which are within the range, but also include vitamin A.
It can be seen that the deficient animal group (1) has a decreased serum calcium concentration. Furthermore, even if a standard amount of vitamin A is continued to be given to the D-deficient animal group (1), which has a decreased serum calcium concentration, the serum calcium concentration does not decrease any further, and the serum calcium concentration does not decrease further. It can be seen that the serum calcium concentration does not increase and maintains its initial low value. By comparing Table 4 with Tables 1 and 3, it can be seen that the decreased serum calcium concentration is restored by administration of vitamin D. By comparing Table 5 with Tables 1, 3, and 4, it can be seen that the decreased serum calcium concentration is also restored when both vitamin D and vitamin A are administered; It can be seen that the serum calcium concentration recovers more slowly than when D was administered. By comparing Table 6 with Table 5, it can be seen that there is no significant difference in the above effects of vitamin A whether a standard amount of vitamin A is given or a triple amount of vitamin A is given. By comparing Table 7 with Tables 1 and 3, it can be seen that the decreased serum calcium concentration can be recovered by administering [1α,25-(OH)2-D3]. By comparing Table 8 with Tables 1, 3, and 7, recovery of decreased serum calcium levels occurs even when providing standard amounts of vitamin A. However, there was no significant difference in the recovery of serum calcium concentration when vitamin A was given or not. This results in
If the recovery of serum calcium concentration is to be moderated, vitamin A should be used rather than vitamin D hormones such as vitamin D2 or D.
It can be seen that it is effective to use it in conjunction with 3. Table 9
By comparing this with Table 4, it can be seen that the decreased serum calcium concentration does not recover to the normal value even if vitamin D is given, if no calcium is ingested.

Various known methods can be used to administer vitamin A in accordance with the present invention. The administration route is generally oral administration, but is not limited to this. Therefore, dosage forms include those suitable for oral administration such as tablets, capsules, powders, and liquids, as well as those by other administration routes such as injections, suppositories, and ointments. Furthermore, when administering vitamin D and vitamin A simultaneously, it is convenient and therefore preferable to administer a preparation containing both of them in a predetermined ratio. Furthermore, it is more preferable to include calcium as well, since this can compensate for the lack of calcium ingested from food.

[0015] The dosage varies depending on symptoms, age, body weight, etc., but in general, when administered to adults, the dosage of vitamin D is 400 IU (0.01 mg) to 50,000 IU (1.
25 mg), and the dose of vitamin A administered at the same time is 2,000 vitamin A units (2 mg).
About 100,000 vitamin A units (100 mg) is preferred. Therefore, the dosage ratio of vitamin D and vitamin A is preferably about 1:1.6 to 1:10,000.

[0016]

[Effects of the Invention] As described above, by administering vitamin A to prevent or treat hypercalcemia symptoms, serum calcium concentration can be lowered relatively easily and safely. Additionally, when administering vitamin D to treat hypocalcemia, administering vitamin A at the same time will suppress the rapid increase in serum calcium concentration and prevent side effects caused by the sudden increase and hypercalcemia symptoms. Therefore, the serum calcium concentration does not necessarily need to be strictly controlled, and thus vitamin D can be administered easily.

Claims (5)

[Claims] 1. A serum calcium concentration adjusting drug characterized by containing vitamin A. 2. A serum calcium concentration adjusting drug characterized by containing vitamin D and vitamin A. 3. The serum calcium concentration adjusting drug according to claim 2, wherein the vitamin D is vitamin D2 and/or vitamin D3. [Claim 4] The content ratio of vitamin D and vitamin A is D
The serum calcium concentration adjusting drug according to claim 2, wherein: A = 1:1.6 to 1:10,000. 5. The serum calcium concentration adjusting drug according to claim 2, further comprising calcium.